Yellow fever in the Americas: the growing concern about new

Yellow fever (YF) is a haemorrhagic viral disease with a high case fatality rate. It is considered a reemerging infectious disease of remarkable importance. During the last outbreaks in Angola (2015-2016) and Brazil (2016-2017), many cases of YF emerged despite high YF vaccination coverage, increasing the risk of major epidemics in the Americas. Several factors, including the vast border and migratory status of Brazil, the widespread distribution of   mosquitoes and the lack of efficient health Aedes policies and surveillance systems, favour this complex epidemiological scenario of reemergence. Therefore, mass vaccination of the population at risk, public health awareness and preparedness are urgently needed in this region. This article describes the current global epidemiological situation of YF, focusing especially on the Americas, as well the risk and vulnerabilities in the region that would be of concern for major expansion to other countries apart from Brazil.


References Introduction
Yellow fever (YF) is a haemorrhagic viral, vector-borne disease with a high case fatality rate (CFR), spread by infected mosquitoes. It has reappeared as a threat to global public health, evidenced by new epidemics in several countries in Africa and South America through autochthonous transmission, and in Asia with imported cases 1 . In Asia, but also Europe and North America, Nevertheless, potential spreads beyond the borders of the endemic countries is a matter of global concern. Currently, there are around 1 billion people, from 49 endemic countries, that are considered at risk 1,2 .

Recent outbreaks
Although relatively wide scale YF vaccination has been applied, a growing number of outbreaks have been documented in several African countries in the last decade. The most recent outbreak occurred in Angola, resulting in 7,344 suspected cases, 962 laboratory-confirmed cases and 137 deaths (with a CFR of 14.2%), and lasting from December 2015 to October 2016 2 . In addition to spread of YF by autochthonous transmission, confirmed imported cases of YF were identified in China and Kenya 1-3 . Other countries, such as Chad, Ghana and Guinea have also reported outbreaks or sporadic cases not linked to the outbreak in Angola 1-3 .
The concern raised from Brazil The geographical spread of the cases in Brazil has led to major concern, because cases are no longer being reported just in the jungle, but also in the most densely populated cities and states such as Minas Gerais and São Paulo. Fortunately, these regions have a long history of high YF vaccination coverage in young people, in contrast with the low vaccination rates in other major urban centres of Brazil 4 .
Although the epidemiology and clinical manifestations of YF should be familiar to healthcare workers in endemic countries, where clinical manifestations can overlap with other acute viral haemorrhagic fevers and other etiologies of the febrile syndrome, a rapid spread of misinformation about this harmful disease in social media and a lack of online training for healthcare workers has been reported in the recent outbreak of 2016-2017 in the Americas 5,6 . In addition to limited health resources, this highlights that early identification could be a challenge in Latin America, as has been observed in the past with Zika and chikungunya virus outbreaks in this region, particularly in countries such as Brazil and Colombia 7,8 .

Conclusions
There seems to be an almost imminent risk of YF outbreaks turning into a large epidemic 9 . Unvaccinated travelers heading to the affected states in Brazil are at risk of spreading the virus in to areas where YF risk factors (human susceptibility, prevalence of competent vector, and animal reservoirs) are present. Ecological factors and enzootics would promote the necessary spillover that would lead to an epidemic [10][11][12]  Mass vaccination of the at-risk population 13 , and public health awareness and preparedness is urgently needed to control the current 2016-2017 outbreak in Brazil and prevent a possible epidemic related to this deadly disease. More studies, as well as new innovative strategies for vector control (e.g. involving community participation), early prevention (e.g. sampling in risk areas to look for asymptomatic subjects), warning and enhanced surveillance (using smart phones), are necessary in order to improve the scenario of this reemerging arboviral threat 14,15 .
Author contributions YOM, AMPB and AJRM all participated in the writing and editing of the manuscript. All authors have agreed to the final content of this article.

Competing interests
No competing interests were disclosed.

Grant information
The author(s) declared that no grants were involved in supporting this work. 2. Please review the punctuation of this sentence: .."In Asia, but also Europe and North America, Nevertheless, potential spreads beyond the borders of the endemic countries is a matter of global concern." RECENT OUTBREAKS 3. Because this section is referring only to information outside of Americas, I respectfully suggest modified the subtitle as: RECENT OUTBREAKS OUTSIDE OF AMERICAS THE CONCERN RAISED FROM BRAZIL In the introduction was stated.."the lack of efficient health policies", however in the development of this idea in this section there is very little (a sentence) about what are the Brazilian health policies for yellow fever or for vector-borne disease. This information could be very useful to go in deep to discussion about the "lack of efficient health policies" CONCLUSIONS 1 2 CONCLUSIONS Again, the statement "the lack of efficient health policies" needs a deeper discussion in the previous section to be included in the conclusions.
I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I strongly recommend to include the comments outlined above.
Is the topic of the opinion article discussed accurately in the context of the current literature? Yes

Are all factual statements correct and adequately supported by citations? Partly
Are arguments sufficiently supported by evidence from the published literature? Yes

Are the conclusions drawn balanced and justified on the basis of the presented arguments? Yes
No competing interests were disclosed.

Competing Interests:
Reviewer Expertise: Infectious diseases

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
Author Response 19 Apr 2017 , Universidad Tecnológica de Pereira, Pereira, Risaralda, Colombia Alfonso Rodriguez-Morales

Dear Dr. Barato
Thank you very much for your valuable assessment and comments. Regard the specific comments:

INTRODUCTION: 1. I consider it to be desirable to include in the introduction the name of the virus (species) which causes yellow fever.
Agree, we will include it.

Please review the punctuation of this sentence: .."In Asia, but also Europe and North
America, Nevertheless, potential spreads beyond the borders of the endemic countries is a matter of global concern." Agree, we will review it.

RECENT OUTBREAKS 3. Because this section is referring only to information outside of Americas, I respectfully suggest modified the subtitle as: RECENT OUTBREAKS OUTSIDE OF AMERICAS
Thanks for your comment, we will modify it.

THE CONCERN RAISED FROM BRAZIL THE CONCERN RAISED FROM BRAZIL
the people of endemic areas not yet entirely immunized with a real 100% vaccine coverage.
For the reader, CFR needs to be expressed as a number of a general historical consensus.

Introduction:
Needs also to document the historical dimension of multiple consistent re-emergence of Yellow fever since it discovery beside the excellence of the vaccine(s). While frequency and size of outbreaks are recently (a decade ago) increasing.
: China emergence needs to be more specific (i.e. risk) from where (climatic zone) Recent outbreaks these imported cases were observed.
: "Concern raised from Brazil" From the general title or this of such chapter section, one is misleading "Americas (title) or Brazil (this section)"? I suggest something like: "From Brazilian experience, a concern of YF risk for the Americas" Line 3: "epicentre:" this needs to be more precise geographically or the sentence clearly linked to the following one, starting by "Indeed, …" Second section, line 4: "a long history of high YF vaccination coverage", I am not sure this is applicable to Minas Gerais's remote areas, at least for "long history". The lack of YF vaccination coverage was raised several times by the Brazilian provincial health authorities back in the early 2000s, unable to reach the remote western zones of the province.
Section 3, line 3, top of the page: to be politically correct we do not use anymore "Latin America" but "South America".
: Main concerns, regarding the YF risk of emergence/re-emergence, seems to be missing:

Conclusions
Vaccine: 1/ The recent outbreaks and the lack of Yellow fever vaccine stock piling (WHO). This needs to be strategized (YF vaccine availability) by the country health authorities and international community. 2/ Also the lifelong protection of the vaccine, its inocuity, and the reduction by 1/10 of the immunity dose are new and of extremely high importance (i.e. for the public & public health).
Biosurveillance needs to be stressed: Mosquito biosurveillance is an important issue to control the epidemic risk, also and specific for South America and have well Haemagogus Sabethes are studied, the risk and ability of (expansion) to transmit the virus in the Americas Aedes albopictus needs to be assessed and an entomological priority set up when needed (i.e. Public health priority in at risk areas).
Trans-border risk. Ultimately traveler's from/to endemic areas need to be covered by a mandatory international certificate of vaccination to protect the borders (trans-border risk).
The long time mystery of the absence of YFV in South East Asia can be also stressed in term of global risk.

Are arguments sufficiently supported by evidence from the published literature?
We would rephrase that, in order to make clear that although in some areas of some countries at risk, there is a high YF vaccination coverage, there are many areas and populations worldwide, where that is low for years (e.g. Nigeria).

Introduction: For the reader, CFR needs to be expressed as a number of a general historical consensus.
We will explain more about the CFR historical reports.
Needs also to document the historical dimension of multiple consistent re-emergence of Yellow fever since it discovery beside the excellence of the vaccine(s). While frequency and size of outbreaks are recently (a decade ago) increasing.
Ok. We will also comment on this, according to your recommendation.
Recent outbreaks: China emergence needs to be more specific (i.e. risk) from where (climatic zone) these imported cases were observed.
Ok. Now is more detailed available information about it, then we will address this in the revised version.
"Concern raised from Brazil": From the general title or this of such chapter section, one is misleading "Americas (title) or Brazil (this section)"? I suggest something like: "From Brazilian experience, a concern of YF risk for the Americas" Well, the concern is for Americas, Brazil is already with epidemics. Then, given that, we will change the title of section to "From Brazilian experience, a concern of YF risk for the Americas".
Line 3: "epicentre:" this needs to be more precise geographically or the sentence clearly linked to the following one, starting by "Indeed, …" Ok, we will correct it.
Second section, line 4: "a long history of high YF vaccination coverage", I am not sure this is applicable to Minas Gerais's remote areas, at least for "long history". The lack of YF vaccination coverage was raised several times by the Brazilian provincial health authorities back in the early 2000s, unable to reach the remote western zones of the province. Agree, we will make such clarification. Section 3, line 3, top of the page: to be politically correct we do not use anymore "Latin America" but "South America". Well, that is not really accurate, both terms are correct. But Latin America includes both Central and South America. You can consult any reference and you will realize this. South America is not exchangeable to Latin America, with this you will be excluding Central America and Mexico.
Conclusions: Main concerns, regarding the YF risk of emergence/re-emergence, seems to be missing: Vaccine: 1/ The recent outbreaks and the lack of Yellow fever vaccine stock piling (WHO). This needs to be strategized (YF vaccine availability) by the country health authorities and international community. This will be included in our new revised version.
2/ Also the lifelong protection of the vaccine, its inocuity, and the reduction by 1/10 of the immunity 2/ Also the lifelong protection of the vaccine, its inocuity, and the reduction by 1/10 of the immunity dose are new and of extremely high importance (i.e. for the public & public health). This too.
Biosurveillance needs to be stressed: Mosquito biosurveillance is an important issue to control the epidemic risk, also Haemagogus and Sabethes are specific for South America and have well studied, the risk and ability of Aedes albopictus (expansion) to transmit the virus in the Americas needs to be assessed and an entomological priority set up when needed (i.e. Public health priority in at risk areas).
We will add comments about this.
Trans-border risk. Ultimately traveler's from/to endemic areas need to be covered by a mandatory international certificate of vaccination to protect the borders (trans-border risk). Ok, agree. We will include comments about this.
The long time mystery of the absence of YFV in South East Asia can be also stressed in term of global risk. Ok, we will make also comments on this. None.

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